JPH0742286B2 - Thiazolidine derivative - Google Patents

Description

TECHNICAL FIELD The present invention relates to a novel thiazolidine derivative useful as a medicine exhibiting a hypoglycemic action.

Conventional branch surgery and the purpose of the present invention. (In the formula, W, U, R ¹ , R ² , R ³ , R ⁴ and n have the same meanings as described below), a thiazolidine derivative having the following formula was synthesized, and the obtained compound exhibits a hypoglycemic action. I found that. [JP-A-60-5
No. 1189 and Japanese Patent Application No. 60-35324] This time, the sulfate ester represented by the following general formula (I) corresponding to the general formula (II) shows a significant hypoglycemic action and the compound of the general formula (II) It was found that it is superior in durability to the above, and was found to be useful as an antidiabetic agent, and the present invention was completed based on these findings.

The novel thiazolidine derivative of the present invention has the general formula And a pharmacologically acceptable salt thereof.

In the above formula, W is a methylene group, a carbonyl group or a formula C =
N-OV group (in the formula, V represents a hydrogen atom, a sulfo group, an acyl group or an alkyl group which may have a substituent), U represents a methylene group, and W represents a carbonyl group or (wherein, V is. showing the same meanings as defined above) wherein C = N-OV group when indicating the may form a double bond together with R ^1, R ¹ having 1 to hydrogen atom or a C A straight-chain or branched-chain alkyl group having 8 is shown, and when W represents a carbonyl group or a formula C = N-OV group (in the formula, V has the same meaning as described above). , U may form a double bond, R ² and R ⁴ are the same or different and each represents a hydrogen atom or a linear or branched alkyl group having 1 to 5 carbon atoms, and R ³ Has 1 to 10 carbon atoms
Is a linear or branched alkyl group having n, and n is an integer of 1 to 3.

In the general formula (I), the alkyl group for R ¹ is preferably, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, hexyl, 1,3-dimethylbutyl,
It is an alkyl group having 1 to 8 carbon atoms such as heptyl, octyl, 1-methylheptyl and 2-ethylhexyl, and the alkyl group for R ³ is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, se.
c-butyl, tert-butyl, pentyl, isopentyl,
Neopentyl, hexyl, 1,1-dimethylbutyl, 1,3-
An alkyl group having 1 to 10 carbon atoms such as dimethylbutyl, heptyl, octyl, 1-methylheptyl, 2-ethylhexyl, 1,1,3,3-tetramethylbutyl, decyl, V, R ² and Examples of the alkyl group for R ⁴ include alkyl groups having 1 to 5 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl and isopentyl.

When V represents an alkyl group having a substituent, the substituent is an aryl group which may have a substituent such as a phenyl group, a p-methylphenyl group, an m-chlorophenyl group, and an o-methoxyphenyl group. Alternatively, an alkoxycarbonyl group such as a carboxyl group, an ethoxycarbonyl group, and a t-butoxycarbonyl group can be given.

When V represents an acyl group, V represents an aliphatic acyl group such as an acetyl group, a benzoyl group, an aromatic acyl group which may have a substituent such as a p-methylbenzoyl group, or a nicotinoyl group. And heterocyclic acyl groups. V is preferably a hydrogen atom, a carboxyalkyl group or an alkoxycarbonylalkyl group, more preferably a hydrogen atom, a carboxymethyl group or 1-
It is a carboxy-1-methylethyl group, preferred as U is a methylene group, and suitable as W is a methylene group, a carbonyl group, and further a methylene group.

The target compound represented by the general formula (I) of the present invention is
According to a conventional method, a non-toxic pharmaceutically acceptable salt can be prepared, and as such a salt, for example, an alkali metal salt such as lithium, sodium or potassium; calcium,
Examples thereof include salts of alkaline earth metals such as barium; aluminum salts; salts of basic amino acids such as lysine and arginine. Also, when the salt represents, for example, an alkali metal salt, it can be in the form of its mono-salt or di-salt.

In the compound (I), when U is a methylene group, the carbon atoms at the 2-position of the chroman ring and the 5-position of the thiazolidine ring are asymmetric carbon atoms, and the isomers based on them are also the isomers of the present invention. Included in the compound. Also,
In the compound (I), when U and R ¹ form a double bond, the carbon atom at the 5-position of the thiazolidine ring is an asymmetric carbon atom, and isomers based thereon are also included in the compound of the present invention.

Furthermore, regarding the thiazolidine moiety of compound (I),
The following tautomers are considered, but these are represented by a single general formula (I).

Examples of the thiazolidine derivative having the general formula (I) obtained according to the present invention include the compounds described below.

The abbreviations in the table represent Pn: Pentyl Oc: Octyl TMB: 1,1,3,3-tetramethylbutyl.

Among the above-exemplified compounds, compound N is preferable
o.1,3,4,18,26,28,29 and 32, the most preferred compounds are compounds No.1,3 and their monosodium salts.

The sulfate ester derivative having the general formula (I) of the present invention has the general formula (In the formula, R ¹ , R ² , R ³ , R ⁴ , W, U and n have the same meanings as described above.) A thiazolidine derivative can be sulfuric acid esterified to be produced.

In carrying out this method, the reaction is carried out by contacting the compound (II) with chlorosulfonic acid in the presence of an organic base such as pyridine, picoline, lutidine or triethylamine according to a conventional method. The reaction temperature is not particularly limited, but usually, heating at 50 to 100 ° C. is preferable.
The reaction time varies depending on the reaction temperature, but is usually 10 minutes to 2 hours. When a solvent is used in this reaction, it may be an aromatic hydrocarbon such as toluene or xylene, an ether such as tetrahydrofuran or dioxane, an ester such as ethyl acetate, a nitrile such as acetonitrile, or a mixed solvent thereof. And nitriles are preferred. The molar ratio of the compound (II) and chlorosulfonic acid used is not particularly limited, but it is 0.5 to 10 mol of chlorosulfonic acid with respect to 1 mol of the compound (II).

After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, after the reaction is completed, the reaction product is washed with a solvent that does not dissolve the reaction product such as petroleum ether or hexane, water is added to the obtained residue, and then an aqueous solution of alkali hydroxide such as sodium hydroxide or potassium hydroxide is added. In addition, adjust the pH to around 6.5, and extract with an organic solvent, or when using a solvent in this reaction, after the reaction is complete, the reaction mixture is poured into ice water and directly extracted with an organic solvent such as ethyl acetate, It can be obtained by distilling the solvent from the extract.

The produced compound represented by the general formula (I) is in a desired form, that is, a free form, a salt form of an organic base such as a pyridinium salt, depending on the acidity or basicity in the reaction system,
It can exist as the mono- or di-alkali salt form and can be isolated in any of the desired forms described above by controlling the acidity or basicity of the system. For example, it can be isolated in the pyridinium salt form, and can be optionally converted into the desired form as described above and isolated by allowing a desired amount of a base such as an alkali hydroxide to act.

Compound (I) may also be produced by esterification reaction of compound (II) with sulfuric acid in the presence of a dehydrating agent. N, N'-dicyclohexylcarbodiimide (DC
C), carbodiimides exemplified by mineral acid salts such as 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide or its hydrochloride.
The hydrochloride salt of -dimethylaminopropyl) -3-ethylcarbodiimide is preferred. The esterification reaction is usually performed in a solvent. Examples of the solvent include aromatic hydrocarbons such as toluene and xylene, ethers such as tetrahydrofuran and dioxane, halogenated hydrocarbons such as dichloromethane and chloroform, nitriles such as acetonitrile, dimethylformamide and dimethylacetamide. Examples of such amides, sulfolane, dimethyl sulfoxide, water and mixed solvents thereof,
Amides are preferred. The molar ratio of the compound (II) and sulfuric acid used is usually 1 to 5 sulfuric acid per 1 mol of the compound (II).
The amount is preferably 1 to 2 mol. The molar ratio of the compound (II) to the dehydrating agent used is usually 1 to 10 mol, preferably 3 to 6 mol, relative to 1 mol of the compound (II). The reaction conditions such as reaction temperature and reaction time will differ depending on the starting materials, solvent, etc. used, but usually the reaction temperature is 0 to 50 ° C., preferably around room temperature, and the reaction time is about 10 minutes to 2 days, It is preferably 1 to 3 hours.

The obtained target compound having the general formula (I) or a salt thereof is obtained by a conventional method, for example, column chromatography,
It can be purified by a recrystallization method, a reprecipitation method or the like.

EFFECTS OF THE INVENTION The thiazolidine derivative of the present invention having the general formula (I) exhibits significant drug efficacy in an antidiabetic pharmacological test. For example, 5- [4- (6-hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy) benzyl] thiazolidine-2,4-dione sulfate ester [Compound No. 1 in Table 1] is , A significant hypoglycemic effect in the hypoglycemic test using KK mice (the hypoglycemic rate at 18 hours after oral administration of 50 mg / kg was 18.9 ± 5.2%), and aldose reduction prepared from bovine lens The enzyme 50% inhibitory concentration is
It showed 5.5 × 10 ⁻⁶ mol.

Furthermore, for example, in a blood (plasma) concentration measurement test in which 5 mg / kg of the above compound No. 1 was orally administered to dogs, a high blood concentration [area value under blood concentration, ▲ AUC ⁸ ₀ ▼: 8.0 ± 1.8 μg・ H / ml]
Was obtained and, in addition, it was persistent.

Therefore, the compound having the general formula (I) and its pharmacologically acceptable salt are useful as an antidiabetic agent for treating diabetes and their complications. Examples of the dosage form include tablets, capsules, granules, powders,
Examples thereof include oral administration methods using syrups and the like, and parenteral administration methods using injections such as subcutaneous injection and intravenous injection, eye drops and suppositories. Although the dose varies depending on the administration method, symptoms, age, etc., for example, oral administration is 30 mg to 3 g per day for an adult, and this can be administered in 2 to 3 divided doses.

Hereinafter, the present invention will be described more specifically with reference to examples.

Example 1a) 5- [4- (6-Hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy) benzyl] thiazolidine-2,4-dione sulfate Chlorosulfonic acid 7.3 g (62.64 mmol) pyridine (2
0 ml) solution, 5- [4- (6-hydroxy-2,5,7,8
-Tetramethylchroman-2-ylmethoxy) benzyl] thiazolidine-2,4-dione [prepared by the method described in JP-A-60-51189] A solution of 5 g (11.32 mmol) of pyridine (10 ml) was added to 70- Heated at 80 ° C for 1 hour. After the reaction was completed, 50 ml of petroleum ether was added to the reaction mixture, the supernatant was removed by decantation, and this operation was repeated twice more. 10 ml of water was added to the obtained residue, and the pH was adjusted to around 6.5 with 2N aqueous sodium hydroxide solution.
It was extracted with ethyl acetate. The ethyl acetate was distilled off under reduced pressure,
The target compound as a white powder with a melting point of 140.5-142.5 ℃
Obtained 5.72 g.

IR spectrum (Nujol) ν cm ^-1 : 3600 to 3300,1270,1050 ¹ H-nmr spectrum (CD ₃ CN) δppm: 7.2 (2H, d), 6.9 (2H, d), 4.6 (1H, dd), 4.0 (1H, d), 3.9 (1H, d), 3.3 (1H, dd), 3.1 (1H, dd), 2.6 (2H, t), 2.19 (3H, s), 2.18 (3H, s), 2.1 ( 1H, m), 2.0 (3H, s), 1.9 (1H, m), 1.4 (3H, s) Mass spectrum (measured by FAB method using m / e, glycerol as matrix): [M + H] ⁺ = 522 [ M−H] ⁻ = 520 from MW = 521 Example 1b) The same starting material used in Example 1a) (270 mg, 0.61 mmol)
To 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (588 mg, 3 mmol), 2.5 ml of dimethylformamide was added to make a suspension, and under ice cooling, concentrated sulfuric acid 50 μl
(0.92 mmol) was added and the mixture was stirred at room temperature for 2 hours. Silica gel column chromatography (eluent:
Benzene: ethanol: ethyl acetate 9: 1: 0.5 (100 ml);
6: 2: 0.5 (100 ml); 6: 3: 0.5 (100 ml); 5: 5: 1 (100 ml), which were successively eluted). Concentrate the eluate under reduced pressure and
After dissolving in 1 ml of methanol, add 3 ml of acetone and
The precipitate was precipitated with 30 ml of ether, collected and dried to obtain 166 mg of the target compound as white powder. The NMR spectrum is shown in Example 1a).
It matched with that obtained in.

Example 2 5- [4- (6-Hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy) benzyl] thiazolidine-2,4-dione Sulfate sodium salt As used in Example 1a). 2.48 g (21.2 mmol) of chlorosulfonic acid was added to an acetonitrile solution (65 ml) of 6.25 g (14.2 mmol) of the same starting material and 3.36 g (42.5 mmol) of pyridine, and the mixture was heated at 82 ° C. for 1 hour. After the reaction was completed, ethyl acetate (375 ml) and water (250 ml) were added to separate the aqueous layer,
The organic layer was dried over anhydrous sodium sulfate. Then, ethyl acetate was distilled off under reduced pressure to obtain crude crystals of a pyridinium salt of a sulfuric ester. The crude crystals are ethyl acetate (125 ml)
And dissolved in water (80 ml), 2N aqueous sodium hydroxide solution
7.4 ml was added. Next, the organic layer was removed, the aqueous layer was cooled, and the resulting precipitate was collected. This was heated and dried under reduced pressure to obtain 5.31 g of the target compound in the form of a pale yellow powder.

Elemental analysis Calculated as C ₂₄ H ₂₆ O ₈ NS ₂ Na ・ 1H ₂ O C, 51.33; H, 5.04; N, 2.49; S, 11.42; Na, 4.09% Measured value C, 51.11; H, 5.12; N, 2.47; S, 11.30; Na, 4.20% Note) Note: By ion chromatography quantitative method.

Examples 3-9 The following compounds were produced according to the procedure of Example 1. The compound showed a different Rt value (retention time in HPLC) from the corresponding starting material. The structure of the compound was confirmed by measuring the molecular weight from FAB mass spectrum according to Example 1.

Front page continuation (72) Inventor Kunihiro Sasahara 1-2-58 Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. (72) Inventor Takebayashi ▲ Toyo Raku 1-2-58 Hiromachi, Shinagawa-ku, Tokyo No. Sankyo Co., Ltd. (56) References JP 62-5980 (JP, A)

Claims (1)

[Claims] 1. A general formula [In the formula, W is a methylene group, a carbonyl group or a formula C = N
-OV group (in the formula, V represents a hydrogen atom, a sulfo group, an acyl group or an alkyl group which may have a substituent), U represents a methylene group, and W represents a carbonyl group or a formula. C = N-OV group (wherein, V is. showing the same meanings as defined above) when indicating the may form a double bond together with R ^1, R ¹ is to 1 the number of hydrogen atoms or carbon 8 When a W is a carbonyl group or a formula C = N-OV group (in the formula, V has the same meaning as described above). A double bond may be formed with U, R ² and R ⁴ are the same or different and each represents a hydrogen atom or a linear or branched alkyl group having 1 to 5 carbon atoms, and R ³ is A linear or branched alkyl group having 1 to 10 carbon atoms,
n represents an integer of 1 to 3. ] And a pharmacologically acceptable salt thereof.